Genetics and Cancer - Familial Adenomatous Polyposis (FAP)

Familial adenomatous polyposis (FAP), also known as familial polyposis coli, adenomatous polyposis coli, or Gardner syndrome, is seen in approximately one in 8,000 individuals. The term "Gardner syndrome" has sometimes been used to refer to patients who manifest extracolonic features.

In its classic form, FAP is characterized by the following:

  • polyposis - the development of multiple benign (noncancerous) adenomatous polyps (>100) in the colon and rectum, which are described as having a "dense carpet-like appearance" on colonoscopy or sigmoidoscopy.
  • early age of onset
    Polyps begin to develop at an average age of 16 years (range of seven to 36 years).
  • a nearly 100 percent risk of colorectal cancer in the absence of treatment for polyposis (colectomy, or surgery to remove the colon)
  • an autosomal dominant pattern of inheritance (vertical transmission through either the maternal and paternal line)
  • an increased risk of other health problems such as polyps in the upper gastrointestinal tract, osteomas (benign bony growths), epidermoid cysts (skin lesions), desmoid tumors (locally invasive tumors that grow aggressively and can be life threatening), congenital hypertrophy of retinal pigment (CHRPE), and dental abnormalities
  • an increased risk of thyroid, small bowel, pancreatic, and stomach cancers, brain tumors and hepatoblastoma (a childhood liver tumor)

A tumor suppressor gene called APC, located on chromosome 5, causes most cases of FAP. Virtually all persons who have a mutation in the APC gene that causes the classic form of FAP will develop colorectal polyps by the fourth or fifth decade of life (without intervention). However, the onset is variable. Consider the following:

Age of Onset People who have a mutant APC gene who will have adenomas in the colon

10 years

15 percent

20 years

75 percent

30 years

90 percent
40 to 50 years virtually all persons with a mutation who have not had any intervention (such as surgery)

Because FAP has such an early age of onset, cancer screening often begins in childhood. In addition, genetic testing of children at risk is a special consideration. Usually, genetic tests are not an option for persons who are considered minors unless there is some type of medical benefit available to justify testing. FAP is an autosomal dominant cancer genetic syndrome, which means that a child whose parent has the condition has a 50/50 chance of inheriting the familial APC gene mutation. There is an equally as likely chance the child will not inherit the familial APC mutation, which would spare the child from having to undergo annual examinations (i.e., sigmoidoscopy) if they were found to be mutation negative. Thus, since genetic testing can have an impact on medical management, genetic testing of children at risk of classic FAP is an option that can be considered.

The APC gene is a tumor suppressor gene, which usually has the job of controlling cell growth and cell death. Everyone has two APC genes (one on each chromosome #5). When a person has an altered, or mutated, APC gene, their risk of developing polyps and their risk of cancer increases.

Both copies of a tumor suppressor gene must be altered, or mutated, before a person will develop polyps or cancer. In FAP, the first mutation is usually inherited from either the mother or the father and is therefore present in all cells of the body. This is called a germline mutation. It is not until the second copy of the gene is mutated in, for instance, a colon cell, that a polyp develops. In order for a benign polyp to become malignant (cancerous), the polyp must acquire mutations in several additional growth control genes. Loss of both copies of APC is just the first step in the process of cancer development. What causes these additional mutations to be acquired is unknown. Possible causes include chemical, physical, or biological environmental exposures or chance errors in cell replication. Since we do not know how to prevent these mutations from occurring, the treatment for classic FAP is a colectomy, a removal of the colon once polyps develop before they become cancerous.

It is important to remember that the APC gene is not located on the sex chromosomes. Therefore, mutations can be inherited from the mother or the father's side of the family. In one third of cases, the APC mutation is "de novo", which means it was not inherited, but occurred for the first time in a family in the person with symptoms. Persons with de novo mutations still transmit them in the same inheritance pattern (autosomal dominant), which means there is a 50/50 chance for them to pass the mutation to a child (regardless of gender).

What are genotype-phenotype variations?

Hundreds of mutations have been found throughout the APC gene. It has long been recognized that some families with APC mutations have different symptoms than others. Studies comparing symptoms in patients with different and similar APC mutations have been done to see if there are any correlations. A correlation between specific mutations and symptoms is called a "genotype-phenotype" correlation. Genotype-phenotype correlation studies for the APC gene have shown that the location of a mutation in the gene provides some information about the types of FAP health problems a person will have. For instance, mutations in certain parts of the gene are associated with an increased rate of desmoid tumors (locally invasive tumors that grow aggressively and can be life threatening), osteomas (benign bony growths), and epidermoid cysts (skin lesions). Where in the gene a mutation lies also provides some information about polyp burden (the number of polyps a person will develop). Even though some correlations exist, there is often variability of symptoms between people who have the same mutation. This is because factors other than the APC mutation (environmental factors, other genetic factors) contribute to the development of polyps and cancer.

What is attenuated FAP?

An attenuated form of familial adenomatous polyposis (AFAP) has been identified. Individuals with AFAP develop fewer than 100 adenomatous polyps (average of 30 polyps) and the polyps are more likely to occur on the right side of the colon than in classic FAP. The risk of developing colon cancer is increased, but the average age of diagnosis is older (50 to 55 years of age) than in the classic form. Some of the other health problems associated with classic FAP also occur in the attenuated form, however, cases of congenital hypertrophy of the retinal pigment (CHRPE) and desmoid tumors are rarely seen.

Mutations in three specific areas of the APC gene have been associated with the AFAP phenotype. The polyp burden (number of polyps developed) and the risk of other FAP manifestations varies depending on in what area the mutation is located.

Unlike FAP, not all persons with an AFAP-associated APC mutation will develop polyps, and the lifetime chance to develop polyps is unknown. The incidence of AFAP is also unknown, but thought to be about the same or less than classic FAP.

What is a I1307K mutation?

One APC mutation in particular, called I1307K, is present in 6 percent of the Ashkenazi Jewish population. This mutation is associated with a 10 percent to 20 percent risk of colorectal cancer (slightly more than double the risk of someone else in the general population). However, people with this mutation do not present with the classic "carpet of polyps" in the colorectum seen in FAP.

What is MYH-associated polyposis (MAP)?

Mutations in the MYH gene increase the chance for an individual to develop multiple colorectal polyps or colorectal cancer. Unlike most polyposis and colorectal cancer disorders, MAP is considered to be an autosomal recessive disorder. This means that individuals with MAP have mutations in both copies of their MYH gene.

The number of polyps in individuals with MAP can range from a few to hundreds. The symptoms of MAP overlap with both familial adenomatous polyposis (FAP) and attenuated FAP. Genetic testing for mutations in the MYH gene is available and should be considered in individuals suspected of having FAP or attenuated FAP who do not have mutation in the APC gene. It is not currently known if individuals with only one MYH mutation have a higher than average risk for colorectal polyps and cancer.

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